Calcium is essential for a number of key functions in the body, both as ionized calcium and a calcium complex (Campell A K. Clin Sci 1987; 72:1-10). Cell behaviour and growth are regulated by calcium. In association with troponin, calcium controls muscle contraction and relaxation (Ebashi S. Proc R Soc Lond 1980; 207:259-86).
Calcium selected channels are a universal feature of the cell membrane and the electrical activity of nerve tissue and the discharge of neurosecretory granules are a function of the balance between intracellular and extra cellular calcium levels (Burgoyne R D. Biochim Biophys Acta 1984; 779:201-16). The secretion of hormones and the activity of key enzymes and proteins are dependent on calcium. Finally calcium as a calcium phosphate complex confers rigidity and strength on the skeleton (Boskey A L. Springer, 1988:171-26). Because bone contains over 99% of the total body calcium, skeletal calcium also serves as the major long-term calcium reservoir.
Calcium salts such as, e.g., calcium carbonate is used as a source of calcium especially for patients suffering from or at risk of osteoporosis. Moreover, calcium carbonate is used as an acid-neutralizing agent in antacid tablets.
Calcium salts like e.g. calcium carbonate is used in tablets and due to the high dose of calcium required, such tablets are often in the form of chewable tablets. It is a challenge to formulate chewable tablets containing a calcium salt, which tablets have a pleasant taste and an acceptable mouthfeel without the characteristic dominating taste or feeling of chalk.
Furthermore, i) the high dose of calcium carbonate (normally 300-600 mg of elemental calcium twice daily, corresponding to 750-1500 mg of calcium carbonate twice daily), ii) in general the inherent poor properties of calcium carbonate with respect to tabletting properties like compactability, calls for the need of adding one or more pharmaceutically acceptable excipients in order to obtain a suitable compactability, and iii) the extremely bad taste or mouthfeel of a calcium salt itself especially with respect to chalkiness make it very difficult to prepare a tablet that has a suitable small size, which is conveniently small for a patient to ingest either by swallowing or chewing. Sufficient taste masking is another major challenge when formulating chewable tablets.
As described in WO 2005/117829, the Applicant has found an easy way for producing tablets containing a physiologically tolerable calcium-containing compound by using a granulate comprising agglomerates of the calcium-containing compound. The granulate is obtained without use of any solvent (e.g. water), but involves the technique of roller compaction of the calcium-containing compound to form agglomerates having suitable properties for further processing into a solid dosage form such as, e.g., tablets.
Calcium carbonate tablets are well-described in the patent literature see e.g. WO 2005/117829, WO 2005/115342, WO 00/028973. From WO 2005/117829 are also known calcium carbonate tablets containing sorbitol and calcium carbonate tablet containing sorbitol and maltitol.
However, it has recently been found that when making calcium carbonate tablets for swallowing, the dissolution profile obtained during or immediate after production of the tablets may change over time. In other words the tablets are not stable with respect to dissolution. As long as the change is within acceptable limit (normally ±10%) the tablets are acceptable. However, the present inventors have observed situations, where there is a dramatic decrease in the dissolution profile, i.e. the release of calcium is i) much slower and/or ii) less complete. The present invention addresses this problem and provides a solution thereto.